WO2014153235A2 - Inhibiteurs de l'arginine méthyltransférase et utilisations de ceux-ci - Google Patents

Inhibiteurs de l'arginine méthyltransférase et utilisations de ceux-ci Download PDF

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WO2014153235A2
WO2014153235A2 PCT/US2014/029750 US2014029750W WO2014153235A2 WO 2014153235 A2 WO2014153235 A2 WO 2014153235A2 US 2014029750 W US2014029750 W US 2014029750W WO 2014153235 A2 WO2014153235 A2 WO 2014153235A2
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optionally substituted
compound
certain embodiments
alkyl
methyl
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PCT/US2014/029750
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WO2014153235A3 (fr
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Richard Chesworth
Lorna Helen Mitchell
Gideon Shapiro
Kevin Wayne Kuntz
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Epizyme, Inc.
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Priority to EP14725571.5A priority Critical patent/EP2970220A2/fr
Priority to US14/775,246 priority patent/US9765035B2/en
Publication of WO2014153235A2 publication Critical patent/WO2014153235A2/fr
Publication of WO2014153235A3 publication Critical patent/WO2014153235A3/fr
Priority to US15/675,341 priority patent/US20180105497A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
  • epigenetic regulation is mediated by selective and reversible modification (e.g. , methylation) of DNA and proteins (e.g. , histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
  • methylation e.g. , methylation
  • proteins e.g. , histones
  • methyltransferases e.g., arginine methyltransferases
  • many of which are associated with specific genetic alterations that can cause human disease are associated with specific genetic alterations that can cause human disease.
  • methyltransferases play a role in diseases such as proliferative disorders, autoimmune disorders, muscular disorders, vascular disorders, metabolic disorders, and neurological disorders.
  • diseases such as proliferative disorders, autoimmune disorders, muscular disorders, vascular disorders, metabolic disorders, and neurological disorders.
  • small molecules that are capable of inhibiting the activity of arginine methyltransferases.
  • Arginine methyltransferases are attractive targets for modulation given their role in the regulation of diverse biological processes. It has now been found that compounds described herein, and pharmaceutically acceptable salts and compositions thereof, are effective as inhibitors of arginine methyltransferases. Such compounds have the general Formula (I):
  • R 1; R 3 , R x , X, Y, and m are as defined herein.
  • compositions which comprise a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • compounds described herein inhibit activity of an arginine methyltransferase (RMT) (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8).
  • RMT arginine methyltransferase
  • methods of inhibiting an arginine methyltransferase comprise contacting the arginine methyltransferase with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the RMT may be purified or crude, and may be present in a cell, tissue, or a subject. Thus, such methods encompass inhibition of RMT activity both in vitro and in vivo.
  • the RMT is wild-type.
  • the RMT is overexpressed.
  • the RMT is a mutant. In certain embodiments, the RMT is in a cell. In certain embodiments, the RMT is in an animal, e.g., a human. In some embodiments, the RMT is expressed at normal levels in a subject, but the subject would benefit from RMT inhibition (e.g., because the subject has one or more mutations in an RMT substrate that causes an increase in methylation of the substrate with normal levels of RMT). In some embodiments, the RMT is in a subject known or identified as having abnormal RMT activity (e.g., overexpression).
  • methods of modulating gene expression in a cell comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the cell in culture in vitro.
  • cell is in an animal, e.g., a human.
  • methods of modulating transcription in a cell comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the cell in culture in vitro.
  • the cell is in an animal, e.g., a human.
  • methods of treating an RMT-mediated disorder e.g., a PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8-mediated disorder
  • an RMT-mediated disorder e.g., a PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8-mediated disorder
  • administering to a subject suffering from an RMT-mediated disorder an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a
  • the RMT-mediated disorder is a proliferative disorder.
  • compounds described herein are useful for treating cancer.
  • compounds described herein are useful for treating breast cancer, prostate cancer, lung cancer, colon cancer, bladder cancer, or leukemia.
  • the RMT-mediated disorder is a muscular disorder.
  • the RMT-mediated disorder is an autoimmune disorder.
  • the RMT-mediated disorder is a neurological disorder.
  • the RMT-mediated disorder is a vascular disorder.
  • the RMT-mediated disorder is a metabolic disorder.
  • methyltransferases in biological and pathological phenomena, the study of intracellular signal transduction pathways mediated by arginine methyltransferases, and the comparative evaluation of new RMT inhibitors.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be used to be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • 3467512-1 be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et ah, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • HPLC high pressure liquid chromatography
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Radical refers to a point of attachment on a particular group. Radical includes divalent radicals of a particular group.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-w alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("Q-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Q-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C ⁇ alkyl”).
  • an alkyl group has 1 to 5 carbon atoms ("Q-s alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
  • Q-6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3- pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n- hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, e.g. , unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents.
  • the alkyl group is unsubstituted C ⁇ o alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted Ci-w alkyl.
  • an alkyl group is substituted with one or more halogens.
  • Perhaloalkyl is a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the alkyl moiety has 1 to 8 carbon atoms ("Q-s perhaloalkyl”).
  • the alkyl moiety has 1 to 6 carbon atoms ("C ⁇ perhaloalkyl”).
  • the alkyl moiety has 1 to 4 carbon atoms (“C ⁇ perhaloalkyl”).
  • the alkyl moiety has 1 to 3 carbon atoms (“Ci_ 3 perhaloalkyl”).
  • the alkyl moiety has 1 to 2 carbon atoms ("C ⁇ perhaloalkyl").
  • all of the hydrogen atoms are replaced with fluoro.
  • all of the hydrogen atoms are replaced with chloro.
  • perhaloalkyl groups include - CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, and the like.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds), and optionally one or more triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2 _ 2 o alkenyl"). In certain embodiments, alkenyl does not comprise triple
  • an alkenyl group has 2 to 10 carbon atoms ("C 2 -io alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2 _5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
  • Examples of C 2 ⁇ alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 ⁇ alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
  • the alkenyl group is unsubstituted C 2 _ 10 alkenyl.
  • the alkenyl group is substituted C 2 -io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds), and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-20 alkynyl"). In certain embodiments, alkynyl does not comprise double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2 -io alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl").
  • an alkynyl group has 2 to 8 carbon atoms ("C 2 - 8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _5 alkynyl”). In some
  • an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ),
  • C 3 2-propynyl
  • C 4 2-butynyl
  • C 4 2-butynyl
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 ⁇ alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents.
  • the alkynyl group is unsubstituted C 2 _ 10 alkynyl.
  • the alkynyl group is substituted C 2 _ 10 alkynyl.
  • fused or “ortho-fused” are used interchangeably herein, and refer to two rings that have two atoms and one bond in common, e.g.,
  • Bridged refers to a ring system containing (1) a bridgehead atom or group of atoms which connect two or more non-adjacent positions of the same ring; or (2) a bridgehead atom or group of atoms which connect two or more positions of different rings of a ring system and does not thereby form an ortho-fused ring, e.g.,
  • Spiro or “Spiro-fused” refers to a group of atoms which connect to the same atom of a carbocyclic or heterocyclic ring system (geminal attachment), thereby forming a ring, e.g.,
  • Spiro-fusion at a bridgehead atom is also contemplated.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3 _ 14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("Q O carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _ 6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _ 6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io
  • C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cg), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the
  • the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, e.g. , unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3 _io carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _ 10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _ 14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (" -io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _g cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl").
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl"). Examples of C 5 _6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3 _ 6 cycloalkyl groups include the aforementioned C 5 _6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3 _g
  • 3467512-1 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3 _io cycloalkyl.
  • the cycloalkyl group is substituted C 3 _io cycloalkyl.
  • Heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • heterocyclyl or heterocyclic refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl").
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the
  • heterocyclyl ring system each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl,
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("Qo aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, e.g. , unsubstituted (an "unsubstituted aryl") or substituted (a
  • substituted aryl with one or more substituents.
  • the aryl group is unsubstituted C 6 -i4 aryl.
  • the aryl group is substituted C 6 -i4 aryl.
  • Heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl").
  • heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • heteroaryl groups that contain one or more nitrogen atoms the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl,
  • the point of attachment can be any carbon or nitrogen atom, as valency permits.
  • Partially unsaturated refers to a group that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined.
  • saturated refers to a group that does not contain a double or triple bond, i.e. , contains all single bonds.
  • alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or
  • substituted alkynyl, "substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • R aa is, independently, selected from C ⁇ o alkyl, C ⁇ o perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
  • each instance of R cc is, independently, selected from hydrogen, C ⁇ o alkyl, C ⁇ o perhaloalkyl, C 2 _ 10 alkenyl, C 2 _ 10 alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Q-6 alkyl, Ci_6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R is, independently, selected from hydrogen, Ci- ⁇ alkyl, Ci-e perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 - ff
  • each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F “ , CI “ , Br “ , ⁇ ), N0 3 " , C10 4 " , OFT, H 2 POf , HSOf , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propano
  • Halo or "halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Amide nitrogen protecting groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3- ⁇ p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitro
  • TBOC l-methyl-l-(4-biphenylyl)ethyl carbamate
  • Bpoc l-(3,5-di-/-butylphenyl)-l- methylethyl carbamate
  • i-Bumeoc 2-(2'- and 4'-pyridyl)ethyl carbamate
  • Pyoc 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, /-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carb
  • Sulfonamide nitrogen protecting groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl- (lO)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan-2-one
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • TMS triethylsilyl
  • TIPS triisopropylsilyl
  • IPDMS dimethylisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • TDMS dimethylthexylsilyl
  • TDMS i-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • dimethylphosphinothioyl dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic SSyynntthheessiiss,, TT.. WW.. GGrreeeennee aanndd PP.. GG.. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds describe herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, quaternary salts.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example, non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys), rodents (e.g., rats and/or mice), reptiles, amphibians,
  • humans e.g., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, ado
  • the non-human animal is a mammal.
  • the non-human animal may be a male or female at any stage of development.
  • a non-human animal may be a transgenic animal.
  • Treating encompasses an action that occurs while a subject is suffering from a condition which reduces the severity of the condition or retards or slows the progression of the condition ("therapeutic treatment”).
  • Treating also encompasses an action that occurs before a subject begins to suffer from the condition and which inhibits or reduces the severity of the condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g. , treat the condition.
  • the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • methyltransferase represents transferase class enzymes that are able to transfer a methyl group from a donor molecule to an acceptor molecule, e.g. , an amino acid residue of a protein or a nucleic base of a DNA molecule.
  • Methytransferases typically use a reactive methyl group bound to sulfur in S-adenosyl methionine (SAM) as the methyl donor.
  • SAM S-adenosyl methionine
  • a methyltransferase described herein is a protein methyltransferase.
  • a methyltransferase described herein is a histone methyltransferase.
  • Histone methyltransferases (HMT) are histone-modifying enzymes, (including histone-lysine N-methyltransferase and histone- arginine N-methyltransferase), that catalyze the transfer of one or more methyl groups to lysine and arginine residues of histone proteins.
  • a methyltransferase described herein is a histone-arginine N-methyltransferase.
  • RMT arginine methyltransferase
  • X is N-R 2 and Y is N;
  • X is N and Y is N-R 2 ;
  • each instance of R is independently selected from the group consisting of hydrogen, halogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or two R groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
  • R4 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, -OR A , -N(R B ) 2 , -SR A , or an oxygen protecting group;
  • n 0, 1, 2, 3, or 4;
  • R 2 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _ 7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy;
  • R 3 is independently hydrogen, Ci_4 alkyl, or C 3 _ 4 carbocylyl
  • R x is independently optionally substituted C 1-4 alkyl or optionally substituted C 3 _ 4 carbocylyl;
  • each instance of R A is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
  • each instance of R is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
  • Cy is independently optionally substituted C 3 _ 7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl.
  • a provided compound is of Formula (II):
  • a provided compound is of Formula (Il-a):
  • a provided compound is of Formula (Il-al):
  • a provided compound is of Formula (II-al-i):
  • a provided compound is of Formula (II-al-ii):
  • a provided compound is of Formula (Il-al-iii)
  • a provided compound is of Formula (Il-al-iv):
  • a provided compound is of Formula (II-al-v):
  • a provided compound is of Formula (II-a2):
  • a provided compound is of Formula (II-a3):
  • a provided compound is of Formula (II-a4):
  • a provided compound is of Formula (II-a4-i):
  • a provided compound is of Formula (II-a5):
  • a provided compound is of Formula (II-a6):
  • a provided compound is of Formula (Il-b):
  • a provided compound is of Formula (Il-bl):
  • a provided compound is of Formula (II-b2):
  • a provided compound is of Formula (II-b2-i):
  • a provided compound is of Formula (II-b3):
  • a provided compound is of Formula (II-c):
  • a provided compound is of Formula (II-cl):
  • a provided compound is of Formula (II-c2):
  • a provided compound is of Formula (II-c2-i):
  • a provided compound is of Formula (II-c3):
  • a provided compound is of Formula (Il-d):
  • a provided compound is of Formula (Il-dl):
  • a provided compound is of Formula (II-d2):
  • a provided compound is of Formula (II-d3):
  • a provided compound is of Formula (II-d4):
  • a provided compound is of Formula (II-d5):
  • X, Y, R 3 , R x , and R 4 are as described herein, and i is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • a provided compound is of Formula (II-d6):
  • X, Y, R , R x , and R 4 are as described herein, and i is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • each instance of Ri is independently selected from the group consisting of hydrogen, halogen, -N 3 , -CN, -N0 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
  • Ri is hydrogen. In some embodiments, Ri is not hydrogen. In some embodiments, Ri is halogen. In certain embodiments, Ri is F. In certain embodiments, Ri is CI. In certain embodiments, Ri is Br. In certain embodiments, Ri is I. In some embodiments,
  • Ri is optionally substituted alkyl. In some embodiments, Ri is optionally substituted alkenyl. In certain embodiments, Ri is optionally substituted alkynyl. In certain embodiments, Ri is optionally substituted C 1-6 alkyl. In certain embodiments, Ri is substituted C 1-6 alkyl. In certain embodiments, Ri is -CF 3 , CHF 2 , or CH 2 F. In certain embodiments, Ri is -C 1-6 alkyl- carbocyclyl. In certain embodiments, Ri is -CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, Ri is unsubstituted Ci_ 6 alkyl.
  • Ri is methyl, ethyl, propyl, butyl, or pentyl. In certain embodiments, Ri is isopropyl, isobutyl, or isopentyl. In certain embodiments, Ri is isobutyl. In some embodiments, Ri is -CN. In some embodiments,
  • Ri is optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • Ri is -N(R B ) 2 . In certain embodiments, Ri is -NHR B . In certain embodiments, Ri is -NH 2 . In certain embodiments, Ri is -OR A . In certain embodiments, Ri is -OH. In certain embodiments, Ri is -OR A , wherein R A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl. In certain embodiments, Ri is -O- isobutylenyl. In certain embodiments, Ri is -OR A , wherein R A is optionally substituted C 1-6 alkyl. In certain embodiments, Ri is -OR A , wherein R A is unsubstituted C 1-6 alkyl.
  • Ri is -O-propyl, -O-isopropyl, -O-isobutyl, or -O-isopentyl.
  • Ri is -OR A , wherein R A is substituted Ci_ 6 alkyl.
  • Ri is -0-Ci- 6 alkyl-0-Ci- 6 alkyl.
  • Ri is -OCH 2 CH 2 OCH 3 or - OCH 2 CH 2 CH 2 OCH 3 .
  • Ri is -0-Ci_ 6 alkyl-carbocyclyl.
  • Ri is -0-CH 2 -cyclobutyl or -0-CH 2 -cyclopropyl.
  • Ri is -0-Ci_ 6 alkyl-heterocyclyl. In certain embodiments, Ri is -0-CH 2 -tetrahydropyranyl or - 0-CH 2 -oxetanyl. In certain embodiments, Ri is -OR A , wherein R A is optionally substituted heterocyclyl. In certain embodiments, Ri is -O-tetrahydropyranyl or -O-oxetanyl. In certain embodiments, Ri is -OR A , wherein R A is optionally substituted aryl. In certain embodiments, Ri is -O-phenyl. In certain embodiments, Ri is -OR A , wherein R A is optionally substituted heteroaryl.
  • R C is independently selected from the group consisting of hydrogen, halogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or two R groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; and R4 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, -OR A , -N(R B ) 2 , -SR A , or an oxygen protecting
  • Z is -0-.
  • Z is - (CH 2 ) n O-, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, Z is -CH 2 0- In certain embodiments, Z is -(CH 2 ) 2 0- In certain embodiments, Z is -(CH 2 ) 3 0- In certain embodiments, Z is -(CH 2 ) 4 0- In certain embodiments, Z is -(CH 2 )sO-. In certain embodiments,
  • Z is -(CH 2 ) 6 0-. In certain embodiments, Z is -(CH 2 ) 7 0-. In certain
  • R 4 is optionally substituted alkynyl. In certain embodiments, R 4 is optionally substituted C 1-6 alkyl. In certain embodiments, R ⁇ is substituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted C 1-6 alkyl. In certain embodiments, R ⁇ is methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl. In certain embodiments, R ⁇ is optionally substituted carbocyclyl. In certain embodiments, R 4 is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R ⁇ is unsubstituted cyclopropyl,
  • R 5 is optionally substituted methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl.
  • R5 is benzyl.
  • R5 is methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl.
  • R 5 is isopropyl.
  • R 5 is optionally substituted aryl. In certain embodiments, R 5 is phenyl. In certain embodiments, R 4 is optionally substituted aryl. In certain embodiments, R 4 is optionally substituted heterocyclyl. In certain embodiments, R 4 is optionally substituted five-membered heterocyclyl. In certain embodiments,
  • R 4 is optionally substituted six-membered heterocyclyl.
  • R 4 is optionally substituted five-membered heteroaryl.
  • R 4 is optionally substituted pyrrole, furan, thiophene, imidazole, pyrazole, isothiazole isoxazole, oxazole ,thiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-oxadiazole, 1,2,4-
  • R 4 is optionally substituted six-membered heteroaryl. In certain embodiments, R4 is optionally substituted six-membered heteroaryl. In certain embodiments, R 4 is optionally substituted pyridine. In certain embodiments, R ⁇ is -OR A . In certain embodiments,
  • R 4 is -OH. In certain embodiments, R 4 is -O-methyl, -O-ethyl, -O-propyl, - O-butyl, -O-isopropyl, or -O-isobutyl.
  • Z is -O- and R 4 is optionally substituted alkyl. In certain embodiments, Z is -O- and R 4 is optionally substituted carbocyclyl. In certain embodiments, Z is -O- and R 4 is optionally substituted aralkyl. In certain embodiments, Z is -O- and R 4 is optionally substituted benzyl. In certain embodiments, Z is -O- and R 4 is optionally unsubstituted benzyl. In certain embodiments, Z is -O- and R 4 is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, Z is -O- and R 4 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, Z is -O- and R 4 is unsubstituted cyclopropyl, cyclobutyl
  • Z is -O- and R 4 is of the formula .
  • Z is -(CH 2 ) n O- and R 4 is optionally substituted alkyl.
  • Z is -(CH 2 ) n O- and R 4 is -OR A .
  • Z is -(CH 2 ) n O- and R 4 is -N(R B ) 2 .
  • Z is -(CH 2 ) n O- and R 4 is -SR A .
  • Z is - (CH 2 ) n O- and R 4 is optionally substituted six-membered heteroaryl.
  • Z is -(CH 2 ) n O- and R 4 is optionally substituted five-membered heteroaryl.
  • Z is -(CH 2 ) n O- and R 4 is optionally substituted six-membered heteroaryl. In certain embodiments, Z is -(CH 2 ) n O- and R 4 is optionally substituted pyrazole. In certain embodiments, Z is -(CH 2 ) S - and R 4 is optionally substituted pyridine. In certain embodiments, Z is -(CH 2 ) S - and R 4 is optionally substituted six-membered heteroaryl. In certain
  • R 4 is optionally substituted pyrazole.
  • Z is -O- and R 4 is of the formula
  • R 4 is of the formula wherein each of V 1; V is independently C or N.
  • R 4 is of the formula
  • R 4 is of the formula . In certain embodiments, R 4
  • R 4 is of the formula In certain embodim the
  • R 4 is of the formula .
  • R 4 is of the for . In certain embodiments, R 4 is
  • p is 0, 1, 2, 3, 4, or 5 as valence permits. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments p is 4. In some embodiments, p is 5. In certain embodiments R 4 is of the
  • R 4 is of the formula
  • R 4 is of the formula .
  • q is 0, 1, or 2.
  • q is 1. In certain embodiments, q is 2.
  • R 4 is of the formula 4 wherein each of A 1; A 2 , A 3 , A 4 , and A5 is independently -C(R ) 2 - , -0-, or -NR 7n -; and R 7 and R 7n are defined herein. In certain embodiments, no more than two of A 1; A 2 , A3, A 4 , and A5 are -0-, or - NR 7n -
  • R 4 is of the formula wherein each of A 1; A 2 , A 3 , and A 4 is independently -C(R 7 ) 2 - , -0-, or -NR 7n -; and R 7 and R 7n are defined herein. In certain embodiments, no more than one of A 1; A 2 , A3, and A is -0-, or -NR 7n -.
  • R 4 is of the formula wherein each of A 1; A 2 ,
  • a 3 , and A 4 is independently -C(R 7 ) 2 - , -0-, or -NR 7n -; and R 7 and R 7n are defined herein. In certain embodiments, no more than two of A 1; A 2 , A3, and A 4 are -0-, or -NR 7n -.
  • R4 is of the formula wherein each of A 1; A 2 , and A3 is independently -C(R ) 2 - , -0-, or -NR 7n -; and R 7 and R 7n are defined herein. In certain embodiments, no more than one of A 1; A 2 , and -O- or -NR 7n -.
  • R 4 is of the formula is -C(R ) 2 - ,
  • R 4 is of
  • each instance of R 7 is independently selected from the group consisting of hydrogen, halogen, -N 3 , -CN, -N0 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
  • R 7 is hydrogen. In some embodiments, R 7 is not hydrogen. In some embodiments, R 7 is halogen. In certain embodiments, R 7 is F. In certain embodiments, R 7 is CI. In certain embodiments, R 7 is Br. In certain embodiments, R 7 is I. In some embodiments, R 7 is optionally substituted alkyl. In some embodiments, R 7 is optionally substituted alkenyl. In certain embodiments, R 7 is optionally substituted alkynyl. In certain embodiments, R 7 is optionally substituted C 1-6 alkyl. In certain embodiments, R 7 is substituted C 1-6 alkyl. In certain embodiments, R 7 is -CF 3 , CHF 2 , or CH 2 F.
  • R 7 is -C 1-6 alkyl-carbocyclyl. In certain embodiments, R 7 is -CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, R 7 is unsubstituted Ci_6 alkyl. In certain embodiments, R 7 is methyl, ethyl, propyl, butyl, or pentyl. In certain embodiments, R 7 is is isopropyl, isobutyl, or isopentyl. In certain embodiments, R 7 is isobutyl. In some embodiments, R 7 is -C 1-6 alkyl-carbocyclyl. In certain embodiments, R 7 is -CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, R 7 is unsubstituted Ci_6 alkyl. In certain embodiments, R 7 is methyl, ethyl, propyl, butyl, or pentyl. In
  • R 7 is -CN. In some embodiments, R 7 is optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R 7 is -N(R B ) 2 . In certain embodiments, R 7 is -NHR B . In certain embodiments, R 7 is -NH 2 . In certain embodiments, R 7 is -OR A . In certain embodiments, R 7 is -OH. In certain embodiments, R 7 is -OR A , wherein R A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl.
  • R 7 is -O-isobutylenyl. In certain embodiments, R 7 is -OR A , wherein R A is optionally substituted C 1-6 alkyl. In certain embodiments, R 7 is -OR A , wherein R A is unsubstituted C 1-6 alkyl. In certain embodiments, R 7 is -O-methyl, -O-ethyl, -O-propyl, -O- butyl, -O-pentyl, -O-isopropyl, -O-isobutyl, or -O-isopentyl. In certain embodiments, two R 7 groups are joined to form an optionally substituted carbocyclic ring. In certain embodiments,
  • two R 7 groups are joined to form an optionally substituted heterocyclic ring.
  • each instance of R 7n is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group.
  • R 7n is hydrogen.
  • R 7n is optionally substituted acyl.
  • R 7n is optionally substituted alkyl.
  • R 7n is optionally substituted C 1-6 alkyl.
  • R 7n is substituted C 1-6 alkyl. In certain embodiments, R 7n is unsubstituted C 1-6 alkyl. In certain embodiments, R 7n is methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl. In certain embodiments, R 7n is optionally substituted alkenyl. In certain embodiments, R 7n is optionally substituted alkynyl. In certain embodiments, R 7n is optionally substituted carbocyclyl. In certain embodiments, R 7n is optionally substituted aryl. In certain embodiments, R 7n is optionally substituted heterocyclyl. In certain embodiments, R 7n is optionally substituted heteroaryl. In certain embodiments, R 7n is optionally substituted alkyl-Cy. In certain embodiments, R 7n is a nitrogen protecting group.
  • i is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits. In certain embodiments, i is 0. In certain embodiments, i is 1. In certain embodiments, i is 2. In certain embodiments, i is 3. In certain embodiments, i is 4. In certain embodiments, i is 5. In certain embodiments, i is 6. In certain embodiments, i is 7. In certain embodiments, i is 8.
  • each instance of R 6 is independently selected from the group consisting of hydrogen, halogen, -N 3 , -CN, -N0 2 , optionally substituted alkyl, optionally
  • R 6 is hydrogen. In some embodiments, R 6 is not hydrogen. In some embodiments, R 6 is halogen. In certain embodiments, R 6 is F. In certain embodiments, R 6 is CI. In certain embodiments, R 6 is Br. In certain embodiments, R 6 is I. In some embodiments, R is optionally substituted alkyl. In some embodiments, R 6 is optionally substituted alkenyl. In certain embodiments, R 6 is optionally substituted alkynyl. In certain embodiments, R 6 is optionally substituted C ⁇ alkyl. In certain embodiments, R 6 is substituted C 1-6 alkyl. In certain embodiments, R 6 is -CF 3 , CHF 2 , or CH 2 F.
  • R 6 is -C 1-6 alkyl- carbocyclyl. In certain embodiments, R 6 is -CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, R 6 is unsubstituted C 1-6 alkyl. In certain embodiments, R 6 is methyl, ethyl, propyl, butyl, or pentyl. In certain embodiments, R 6 is isopropyl, isobutyl, or isopentyl. In certain embodiments, Ri is isobutyl. In some embodiments, R 6 is -CN. In some
  • R 6 is optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R 6 is -N(R B ) 2 . In certain embodiments, R 6 is -NHR B . In certain embodiments, Ri is -NH 2 . In certain embodiments, R 6 is -OR A . In certain embodiments, R 6 is -OH. In certain embodiments, R 6 is -OR A , wherein R A is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl. In certain embodiments, R 6 is -O- isobutylenyl. In certain embodiments, R 6 is -OR A , wherein R A is optionally substituted Ci_6 alkyl.
  • R 6 is -OR A , wherein R A is unsubstituted Ci_6 alkyl. In certain embodiments, R 6 is -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -O-pentyl, -O-isopropyl, -O- isobutyl, or -O-isopentyl.
  • R 2 is hydrogen, optionally substituted Ci_6 alkyl, optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 6 alkynyl, optionally substituted C 3 _7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl; or optionally substituted C 1-4 alkyl-Cy, wherein Cy is optionally substituted C 3 _ 7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. As defined generally above, each instance of Cy is independently
  • Cy is optionally substituted C 3 _ 7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl.
  • Cy is optionally substituted C 3 _ 7 cycloalkyl.
  • Cy is optionally substituted 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy is oxetane, tetrahydrofuran, or
  • Cy is optionally substituted aryl. In some embodiments, Cy is optionally substituted phenyl. In some embodiments, Cy is unsubstituted phenyl. In some embodiments, Cy is optionally substituted heteroaryl having 1-3
  • heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy is optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms
  • R 2 is In some embodiments, R 2 is .
  • R 3 is hydrogen, C 1-4 alkyl, or C 3 _ 4 cycloalkyl.
  • R is hydrogen.
  • R is C 1-4 alkyl.
  • R is methyl, ethyl, propyl, butyl, or pentyl.
  • R is isopropyl, isobutyl, or isopentyl.
  • R 3 is isobutyl.
  • R 3 is C 3 _ 4 cycloalkyl.
  • R 3 is cyclopropyl.
  • R is cyclobutyl.
  • R x is optionally substituted C 1-4 alkyl or optionally substituted C 3 _ 4 cycloalkyl.
  • R x is unsubstituted C 1-4 alkyl.
  • R x is methyl.
  • R x is ethyl.
  • R x is isopropyl.
  • R x is propyl.
  • R x is butyl.
  • R x is substituted C 1-4 alkyl.
  • R x is C 1-4 alkyl
  • R x is hydroxyethyl or methoxyethyl. In certain embodiments, R x is optionally substituted C 3 _ 4 cycloalkyl. In certain embodiments, R x is unsubstituted C 3 _ 4 cycloalkyl. In certain embodiments, R x is substituted cyclopropyl. In certain embodiments, R x is unsubstituted cyclopropyl. In certain embodiments, R x is substituted cyclobutyl. In certain embodiments, R x is unsubstituted cyclobutyl.
  • m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.
  • each instance of R A is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom.
  • R A is hydrogen.
  • R A is optionally substituted acyl.
  • R A is optionally substituted alkyl.
  • R A is optionally substituted C 1-6 alkyl. In certain embodiments, R A is substituted C 1-6 alkyl. In certain embodiments, R A is unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl. In certain embodiments, R A is optionally substituted alkenyl. In certain embodiments, R A is optionally substituted alkynyl. In certain embodiments, R A is optionally substituted carbocyclyl. In certain embodiments, R A is optionally substituted aryl. In certain embodiments, R A is optionally substituted
  • R A is optionally substituted heteroaryl. In certain embodiments, R A is optionally substituted alkyl-Cy. In certain embodiments, R A is an oxygen protecting group. In certain embodiments, R A is a sulfur protecting group.
  • each instance of R B is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.
  • R is hydrogen.
  • R B is optionally substituted acyl. In certain embodiments, R B is optionally
  • R is optionally substituted Ci_6 alkyl.
  • R B is substituted C ⁇ alkyl.
  • R B is unsubstituted C 1-6 alkyl.
  • R is methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or isopentyl.
  • R is optionally substituted alkenyl.
  • R B is optionally substituted alkynyl.
  • R B is optionally substituted carbocyclyl.
  • R is optionally substituted aryl.
  • R B is optionally substituted heterocyclyl. In certain embodiments, R B is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted alkyl- Cy. In certain embodiments, R is a nitrogen protecting group. In certain embodiments, two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.
  • each of A 1; A 2 , A3, A 4 , and A5 is independently - C(R 7 ) 2 - , -0-, or -NR 7n -; and R 7 and R 7n are defined herein.
  • no more than two of A 1; A 2 , A 3 , A 4 , and A5 are -0-, or -NR 7n -.
  • no more than one of A 1; A 2 , A3, A 4 , and A5 are -0-, or -NR 7n -.
  • Ai is - CH 2 -.
  • Ai is -0-.
  • Ai is -NR 7n -.
  • a 2 is -CH 2 - In certain embodiments, A 2 is -0-. In certain embodiments, A 2 is -NR 7n -. In certain embodiments, A 3 is -CH 2 - In certain embodiments, A 3 is -0-. In certain embodiments, A3 is -NR 7n -. In certain embodiments, A 4 is -CH 2 - In certain embodiments, A 4 is -0-. In certain embodiments, A 4 is -NR 7n -. In certain embodiments, A5 is -CH 2 - In certain embodiments, A5 is -0-. In certain embodiments, A5 is -NR 7n -. In certain embodiments, Ai is -CH 2 -; and A 2 , A 3 , A 4 , and A5 are -CH 2 -. In certain embodiments,
  • Ai is -0-; and A 2 , A3, A 4 , and A5 are -CH 2 -. In certain embodiments, Ai is - NR 7n -; and A 2 , A3, A*, and A5 are -CH 2 -. In certain embodiments, A 2 is -CH 2 -; and Ai, A3, A 4 , and A5 are -CH 2 - In certain embodiments, A 2 is -0-; and Ai, A 3 , A 4 , and A5 are -CH 2 - In certain embodiments, A 2 is -NR 7n -; and Ai, A 3 , A 4 , and A5 are -CH 2 -.
  • A3 is -CH 2 -; and A 2 , Ai, A*, and A5 are -CH 2 -. In certain embodiments, A3 is -0-; and A 2 , Ai, A 4 , and A5 are -CH 2 -. In certain embodiments, A3 is -NR 7n -; and A 2 , Ai, A 4 , and A5 are -CH 2 -.
  • a 4 is -CH 2 -; and A 2 , A 3 , Ai, and A5 are - CH 2 - In certain embodiments, A 4 is -0-; and A 2 , A 3 , Ai, and A5 are -CH 2 - In certain embodiments, A 4 is -NR 7n -; and A 2 , A3, Ai, and A5 are -CH 2 -. In certain embodiments, A5 is -CH 2 -; and A 2 , A3, A 4 , and Ai are -CH 2 -. In certain embodiments, A5 is -0-; and A 2 , A3, A 4 , and Ai are -CH 2 -.
  • A5 is -NR 7n -; and A 2 , A 3 , A 4 , and Ai are - CH 2 -. In certain embodiments Ai is -C(R 7 ) 2 - ; A 2 , A 3 , A 4 , and A5 are -CH 2 -; and two R 7
  • 3467512-1 groups are joined to form an optionally substituted carbocyclic or heterocyclic ring.
  • Ai is -C(R ) 2 - ; A 2 , A3, A 4 , and A5 are -CH 2 -; and two R 7 groups are joined to form an unsubstituted carbocyclic ring.
  • Ai is -C(R 7 ) 2 - ; A 2 , A 3 , A*, and A5 are -CH 2 -; and two R 7 groups are joined to form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.
  • a provided compound is a compound listed in Table 1A or Table IB, or a pharmaceutically acceptable salt thereof.
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8). In certain embodiments, a provided compound inhibits wild-type PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8. In certain embodiments, a provided compound inhibits a mutant RMT. In certain embodiments, a provided compound inhibits PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8, e.g., as measured in an assay described herein. In certain embodiments, the RMT is from a human. In certain embodiments, a provided compound inhibits an RMT (e.g.
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 10 ⁇ .
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 1 ⁇ .
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) at an IC 50 less than or equal to 0.1 ⁇ .
  • a provided compound inhibits an RMT (e.g.
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 10 ⁇ . In certain embodiments, a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 12 ⁇ . In certain embodiments, a provided compound inhibits an RMT (e.g.
  • a provided compound inhibits PRMTl in a cell at an EC 30 less than or equal to 3 ⁇ .
  • a provided compound inhibits PRMTl in a cell at an EC 30 less than or equal to 12 ⁇ .
  • a provided compound inhibits PRMTl in a cell at an EC 3 o less than or equal to 3 ⁇ .
  • a provided compound inhibits an RMT (e.g., PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) in a cell at an EC 3 o less than or equal to 1 ⁇ .
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 1 ⁇ .
  • a provided compound inhibits an RMT (e.g. , PRMTl, PRMT3, CARMl, PRMT6, and/or PRMT8) in a cell at an EC 30 less than or equal to 3
  • a provided compound inhibits cell proliferation at an EC 50 less than or equal to 10 ⁇ . In certain embodiments, a provided compound inhibits cell proliferation at an EC 50 less than or equal to 1 ⁇ . In certain embodiments, a provided compound inhibits cell proliferation at an EC 50 less than or equal to 0.1 ⁇ .
  • RMT can be wild- type, or any mutant or variant.
  • compositions comprising a compound described herein, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein, and optionally a pharmaceutically acceptable excipient.
  • a compound described herein, or salts thereof may be present in various forms, such as amorphous, hydrates, solvates, or polymorphs.
  • a provided composition comprises two or more compounds described herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount.
  • the effective amount is an amount effective for inhibiting an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8). In certain embodiments, the effective amount is an amount effective for treating an RMT- mediated disorder (e.g., a PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8-mediated disorder). In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to prevent an RMT-mediated disorder.
  • an RMT e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8-mediated disorder.
  • compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired.
  • solvents diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a compound described herein (the "active ingredient") into association with a carrier
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions of the present disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • a pharmaceutical composition described herein is sterilized.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cell
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-
  • 3467512-1 gluconic acid calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer' s solution, ethyl alcohol, and mixtures thereof.
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents,
  • the compounds described herein are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the compounds described herein with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates,
  • the dosage form may comprise buffering agents.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a provided compound may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any desired preservatives and/or buffers as can be required.
  • a pharmaceutically acceptable carrier and/or any desired preservatives and/or buffers as can be required.
  • the present disclosure encompasses the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a
  • formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for buccal
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a provided pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the
  • eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of provided compositions will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • 3467512-1 administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g. , two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • a compound described herein may be administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • a compound described herein is administered one or more times per day, for multiple days. In some embodiments, the dosing regimen is continued for days, weeks, months, or years.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • a compound or composition provided herein is administered in combination with one or more additional therapeutically active agents that improve its bioavailability, reduce and/or modify its metabolism, inhibit its excretion, and/or modify its distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • the additional therapeutically active agent is a compound of Formula (I).
  • the additional therapeutically active agent is not a compound of Formula (I).
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of a provided compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized
  • Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • peptides e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (
  • an additional therapeutically active agent is prednisolone, dexamethasone, doxorubicin, vincristine, mafosfamide, cisplatin, carboplatin, Ara-C, rituximab, azacitadine, panobinostat, vorinostat, everolimus, rapamycin, ATRA (all- trans retinoic acid), daunorubicin, decitabine, Vidaza, mitoxantrone, or IBET- 151.
  • kits e.g. , pharmaceutical packs
  • the kits provided may comprise a provided pharmaceutical composition or compound and a container (e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second
  • 3467512-1 container comprising a pharmaceutical excipient for dilution or suspension of a provided pharmaceutical composition or compound.
  • a provided pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.
  • a provided kits further includes instructions for use.
  • RMT e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8
  • methods of treating an RMT-mediated disorder in a subject comprise administering an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof), to a subject in need of treatment.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject is suffering from a RMT-mediated disorder.
  • the subject is susceptible to a RMT-mediated disorder.
  • RMT-mediated disorder means any disease, disorder, or other pathological condition in which an RMT (e.g., PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8) is known to play a role. Accordingly, in some embodiments, the present disclosure relates to treating or lessening the severity of one or more diseases in which an RMT is known to play a role.
  • the present disclosure provides a method of inhibiting an RMT comprising contacting the RMT with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof.
  • the RMT may be purified or crude, and may be present in a cell, tissue, or subject.
  • the method is an in vitro method, e.g., such as an assay method. It will be understood by one of ordinary skill in the art that inhibition of an RMT does not necessarily require that all of the RMT be occupied by an inhibitor at once.
  • Exemplary levels of inhibition of an RMT include at least 10% inhibition, about 10% to about 25% inhibition, about 25% to about 50% inhibition, about 50% to about 75% inhibition, at least 50% inhibition, at least 75% inhibition, about 80% inhibition, about 90% inhibition, and greater than 90% inhibition.
  • a method of inhibiting RMT activity in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein
  • 3467512-1 e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • a method of modulating gene expression in a cell which comprises contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the cell in culture in vitro.
  • the cell is in an animal, e.g., a human.
  • the cell is in a subject in need of treatment.
  • a method of modulating transcription in a cell which comprises contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the cell in culture in vitro.
  • the cell is in an animal, e.g., a human.
  • the cell is in a subject in need of treatment.
  • a method is provided of selecting a therapy for a subject having a disease associated with an RMT-mediated disorder or mutation comprising the steps of determining the presence of an RMT-mediated disorder or gene mutation in an RMT gene (e.g., a PRMT1, PRMT3, CARM1, PRMT6, and/or PRMT8 gene) or and selecting, based on the presence of an RMT-mediated disorder a gene mutation in the RMT gene a therapy that includes the administration of a provided compound.
  • the disease is cancer.
  • a method of treatment for a subject in need thereof comprising the steps of determining the presence of an RMT-mediated disorder or a gene mutation in the RMT gene and treating the subject in need thereof, based on the presence of a RMT-mediated disorder or gene mutation in the RMT gene with a therapy that includes the administration of a provided compound.
  • the subject is a cancer patient.
  • a compound provided herein is useful in treating a proliferative disorder, such as cancer.
  • a proliferative disorder such as cancer.
  • protein arginine methylation by PRMTs is a modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others; and overexpression of PRMTs within these pathways is often associated with various cancers.
  • compounds which inhibit the action of PRMTs, as provided herein are effective in the treatment of cancer.
  • compounds provided herein are effective in treating cancer through the inhibition of PRMT1.
  • PRMT1 overexpression has been
  • PRMT1 specifically deposits an asymmetric dimethylarginine (aDMA) mark on histone H4 at arginine 3 (H4R3me2a), and this mark is associated with transcription activation.
  • aDMA asymmetric dimethylarginine
  • H4R3me2a histone H4 at arginine 3
  • the methylation status of H4R3 positively correlates with increasing tumor grade and can be used to predict the risk of prostate cancer recurrence (Seligson et ah, Nature 2005 435, 1262-1266).
  • inhibitors of PRMT1, as described herein are useful in treating cancers associated with the methylation status of H4R3, e.g., prostate cancer.
  • the methylarginine effector molecule TDRD3 interacts with the H4R3me2a mark, and overexpression of TDRD3 is linked to poor prognosis for the survival of patients with breast cancer (Nagahata et ah, Cancer Sci. 2004 95, 218-225).
  • inhibitors of PRMT1, as described herein are useful in treating cancers associated with overexpression of TDRD3, e.g., breast cancer, as inhibition of PRMT1 leads to a decrease in methylation of H4R3, thereby preventing the association of overexpressed TDRD3 with H4R3me2a.
  • PRMT1 is known to have non-histone substrates.
  • PRMT1 when localized to the cytoplasm, methylates proteins that are involved in signal transduction pathways, e.g., the estrogen receptor (ER).
  • ER estrogen receptor
  • PRMT1 methylates ERa
  • SRC a proto-oncogene tyrosine- protein kinase
  • FK focal adhesion kinase
  • inhibitors of PRMT1 are useful in treating cancers associated with ERa methylation, e.g., breast cancer.
  • PRMT1 has been shown to be involved in the regulation of leukemia development.
  • SRC-associated in mitosis 68 kDa protein is a well-characterized PRMT1 substrate, and when either SAM68 or PRMT1 is fused directly to the myeloid/lymphoid leukemia (MLL) gene, these fusion proteins can activate MLL oncogenic properties,
  • inhibitors of PRMT1, as described herein are useful in treating cancers associated with SAM68 methylation, e.g., leukemia.
  • PRMT1 is implicated in leukemia development through its interaction with AE9a, a splice isoform of AML1-ETO (Shia et al, Blood 2012 119:4953-62).
  • inhibitors of PRMT1 are useful in treating cancers associated with AML1-ETO, e.g., leukemia.
  • the inhibition of PRMT1, e.g., by compounds described herein is beneficial in the treatment of cancer.
  • compounds provided herein are effective in treating cancer through the inhibition of PRMT3.
  • the DAL1 tumor suppressor protein has been shown to interact with PRMT3 and inhibits its methyltransferase activity (Singh et al., Oncogene 2004 23, 7761-7771).
  • Epigenetic downregulation of DAL1 has been reported in several cancers (e.g., meningiomas and breast cancer), thus PRMT3 is expected to display increased activity, and cancers that display DAL1 silencing may, in some aspects, be good targets for PRMT3 inhibitors, e.g., those described herein.
  • the inhibition of PRMT3, e.g., by compounds described herein is beneficial in the treatment of cancer.
  • compounds provided herein are effective in treating cancer through the inhibition of PRMT4, also known as CARM1.
  • PRMT4 levels have been shown to be elevated in castration-resistant prostate cancer (CRPC), as well as in aggressive breast tumors (Hong et al., Cancer 2004 101, 83-89; Majumder et al., Prostate 2006 66, 1292-1301).
  • CRPC castration-resistant prostate cancer
  • inhibitors of PRMT4, as described herein are useful in treating cancers associated with PRMT4 overexpression.
  • PRMT4 has also been shown to affect ERa-dependent breast cancer cell differentiation and proliferation (Al-Dhaheri et al., Cancer Res. 2011 71, 2118-2128), thus in some aspects PRMT4 inhibitors, as described herein, are useful in treating ERa-dependent breast cancer by inhibiting cell differentiation and proliferation .
  • PRMT4 has been shown to be recruited to the promoter of E2F1 (which encodes a cell cycle regulator) as a
  • PRMT4- mediated upregulation of E2F1 expression may contribute to cancer progression and chemoresistance as increased abundance of E2F1 triggers invasion and metastasis by activating growth receptor signaling pathways, which in turn promote an antiapoptotic tumor environment (Engelmann and Piitzer, Cancer Res 2012 72; 571).
  • the inhibition of PRMT4, e.g., by compounds provided herein is useful in treating cancers associated with E2F1 upregulation.
  • the inhibition of PRMT4, e.g., by compounds described herein is beneficial in the treatment of cancer.
  • compounds provided herein are effective in treating cancer through the inhibition of PRMT6.
  • PRMT6 has been reported to be overexpressed in a number of cancers, e.g., bladder and lung cancer (Yoshimatsu et ah, Int. J. Cancer 2011 128, 562-573).
  • the inhibition of PRMT6, by compounds provided herein is useful in treating cancers associated with PRMT6
  • PRMT6 is primarily thought to function as a transcriptional repressor, although it has also been reported that PRMT6 functions as a co-activator of nuclear receptors.
  • PRMT6 suppresses the expression of thrombospondin 1 (TSP1; also known as THBS1; a potent natural inhibitor of angiogenesis and endothelial cell migration) and p21 (a natural inhibitor of cyclin dependent kinase), thereby contributing to cancer development and progression (Michaud-Levesque and Richard, J. Biol. Chem. 2009 284, 21338-21346; Kleinschmidt et al., PLoS ONE 2012 7, e41446).
  • TSP1 thrombospondin 1
  • p21 a natural inhibitor of cyclin dependent kinase
  • the inhibition of PRMT6, by compounds provided herein is useful in treating cancer by preventing the repression of THBsl and/or p21.
  • the inhibition of PRMT6, e.g., by compounds described herein is beneficial in the treatment of cancer.
  • compounds provided herein are effective in treating cancer through the inhibition of PRMT8.
  • deep-sequencing efforts of cancer genomes e.g., COSMIC
  • COSMIC cancer genomes
  • PRMT8 is reported to be the most mutated.
  • 15 carry mutations in the PRMT8 coding region 15 carry mutations in the PRMT8 coding region, and nine of these result in an amino acid change (Forbes et al., Nucleic Acids Res. 2011 39, D945-D950).
  • PRMT8 Because of its high rate of mutation in cancer, PRMT8 is thought to contribute to the initiation or progression of cancer.
  • the inhibition of PRMT8, e.g., by compounds described herein is beneficial in the treatment of cancer.
  • compounds described herein are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma;
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangio sarcom
  • bronchus cancer carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar
  • T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
  • panniculitis-like T-cell lymphoma anaplastic large cell lymphoma
  • a mixture of one or more leukemia/lymphoma as described above and multiple myeloma (MM)
  • heavy chain disease e.g., alpha chain disease, gamma chain disease, mu chain disease
  • hemangioblastoma e.g., hemangioblastoma
  • inflammatory myofibroblastic tumors e.g., immunocytic amyloidosis
  • kidney cancer e.g., nephroblastoma a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis CML
  • chronic neutrophilic leukemia CML
  • hypereosinophilic syndrome HES
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • NF neurofibromatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), mel
  • MMH histiocytoma
  • liposarcoma malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma
  • testicular cancer e.g., seminoma, testicular embryonal carcinoma
  • thyroid cancer e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
  • urethral cancer e.g., Paget' s disease of the vulva.
  • a compound provided herein is useful in treating diseases associated with increased levels of circulating asymmetric dimethylarginine (aDMA), e.g. , cardiovascular disease, diabetes, kidney failure, renal disease, pulmonary disease, etc.
  • aDMA asymmetric dimethylarginine
  • Circulating aDMA is produced by the proteolysis of asymmetrically dimethylated proteins.
  • PRMTs which mediate aDMA methylation include, e.g., PRMTl, PRMT3, PRMT4, PRMT6, and PRMT8.
  • aDMA levels are directly involved in various diseases as aDMA is an
  • NOS nitric oxide synthase
  • NO functions as a potent vasodilator in endothelial vessels, and as such inhibiting its production has major consequences on the cardiovascular system.
  • PRMT1 is a major enzyme that generates aDMA
  • the dysregulation of its activity is likely to regulate cardiovascular diseases (Boger et ah, Ann. Med. 2006 38: 126-36), and other pathophysiological conditions such as diabetes mellitus (Sydow et ah, Vase. Med.
  • the inhibition of PRMTs results in the decrease of circulating aDMA, which is beneficial in the treatment of diseases associated with increased levels of circulating aDMA, e.g., cardiovascular disease, diabetes, kidney failure, renal disease, pulmonary disease, etc.
  • a compound described herein is useful for treating or preventing vascular diseases.
  • a compound provided herein is useful in treating metabolic disorders.
  • PRMT1 has been shown to enhance mRNA levels of FoxOl target genes in gluconeogenesis, which results in increased hepatic glucose production, and knockdown of PRMT1 promotes inhibition of FoxOl activity and thus inhibition of hepatic gluconeogenesis (Choi et al., Hepatology 2012 56: 1546-56).
  • genetic haploinsufficiency of Prmtl has been shown to reduce blood glucose levels in mouse models.
  • the inhibition of PRMT1, e.g., by compounds described herein is beneficial in the treating of metabolic disorders, such as diabetes.
  • a provided compound is useful in treating type I diabetes.
  • a provided compound is useful in treating type II diabetes.
  • a compound provided herein is useful in treating muscular dystrophies.
  • PRMT1 methylate the nuclear poly(A)-binding protein (PABPNl) in a region located near its C-terminus (Perreault et al., J. Biol. Chem. 2007 282:7552-62). This domain is involved in the aggregation of the PABPNl protein, and abnormal aggregation of this protein is involved in the disease oculopharyngeal
  • CARM1 is also the most abundant PRMT expressed in skeletal muscle cells, and has been found to selectively control the pathways modulating glycogen metabolism, and associated AMPK (AMP-activated protein kinase) and p38 MAPK (mitogen-activated protein kinase) expression. See, e.g., Wang et al., Biochem (2012) 444:323-331.
  • inhibitors of CARM1, as described herein are useful in treating metabolic disorders, e.g., for example skeletal muscle metabolic disorders, e.g., glycogen and glucose metabolic disorders.
  • Exemplary skeletal muscle metabolic disorders include, but are not limited to, Acid Maltase Deficiency (Glycogenosis type 2; Pompe disease), Debrancher deficiency (Glycogenosis type 3), Phosphorylase deficiency (McArdle's; GSD 5), X-linked syndrome (GSD9D), Autosomal recessive syndrome (GSD9B), Tarui's disease (Glycogen storage disease VII; GSD 7), Phosphoglycerate Mutase deficiency (Glycogen storage disease X; GSDX; GSD 10), Lactate dehydrogenase A deficiency (GSD 11), Branching enzyme deficiency (GSD 4), Aldolase A (muscle) deficiency, ⁇ -Enolase deficiency, Triosephosphate isomerase (TIM) deficiency, Lafora's disease (Progressive myoclonic epilepsy 2), Glycogen storage disease (Mus
  • Glycogenin Deficiency (GSD 15).
  • a compound provided herein is useful in treating autoimmune disease.
  • PRMT inhibitors may be valuable for the treatment of autoimmune diseases, e.g., rheumatoid arthritis.
  • PRMTs are known to modify and regulate several critical immunomodulatory proteins. For example, post-translational modifications (e.g., arginine methylation), within T cell receptor signaling cascades allow T lymphocytes to initiate a rapid and appropriate immune response to pathogens.
  • PRMT1 and/or PRMT4 inhibitors are useful in treating autoimmune disease by decreasing the transcription of p65 target genes like TNFa. These examples demonstrate an important role for arginine methylation in
  • a compound provided herein is useful in treating neurological disorders, such as amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • TLS/FUS a gene involved in ALS, TLS/FUS, often contains mutated arginines in certain familial forms of this disease (Kwiatkowski et ah, Science 2009 323: 1205-8). These mutants are retained in the cytoplasm, which is similar to reports documenting the role arginine methylation plays in nuclear-cytoplasmic shuffling (Shen et ah, Genes Dev. 1998 12:679-91).
  • PRMT e.g., PRMT1
  • TLS/FUS is methylated on at least 20 arginine residues
  • compounds of Formula (I) can be prepared using methods shown in Scheme 1.
  • Scheme 1 shows a general synthesis route to indazole compounds of Formula (I), wherein R and X' are either the same as Ri and X or are substituents which serve as precursors for synthetic conversion to Ri and X wherein R 1; R x , R 3 , X and Y are as defined above.
  • indazole-3-carboxylates of general formula XI are reduced to alcohol intermediates of general formula XII using standard conditions, for example, using LiAlH 4 in THF under cooling or at room temperature.
  • Intermediates XII can then be converted to indazole-3-carboxaldehydes of general formula XIII by oxidation using standard conditions, for example, using Mn0 2 in an aprotic solvent at room or elevated temperature.
  • Reaction of intermediates XIII with mono-Boc protected ethylenediamines of general formula XIV under reductive amination conditions e.g. sodium cyanoborohydride and catalytic acid such as acetic acid
  • an appropriate solvent e.g. methanol
  • either Rr and X' can be converted as required to the Ri and X or substituents present in final compounds of Formula (I).
  • compounds with Ri as an alkoxy group can be synthesized by deprotection of the alkylation intermediates of formula XV (e.g. deprecation
  • a suitable alkylbromide or iodide in the presence of an appropriate base (e.g. potassium carbonate) in an organic solvent (e.g. tetrahydrofuran) at room or elevated temperature.
  • an appropriate base e.g. potassium carbonate
  • an organic solvent e.g. tetrahydrofuran
  • the N-Boc protecting can be removed with an acid (e.g. HC1) in a suitable organic solvent (e.g. ethanol) to give compounds of formula I.
  • Indazole-3-carboxylates of general formula XI may be prepared from 3- unsubstituted indazole starting materials of formula XXI as depicted in Scheme 2. lodination of starting materials XXI, for example, using N-iodosuccinimide in DMF at room temperature can be used to prepare 3-iodoindazoles of general formula XII.
  • X' in the intermediates of formulas XI, XII, XIII and XV may bear a protecting group (e.g. THP) which is either removed concomitantly in the final Boc deprotection step, or may optionally be converted in separate additional deprotection and alkylation steps to the final X group.
  • THP a protecting group
  • Scheme 3 uses a THP protected intermediate with Ri as an alkoxy group.
  • THP group Deprotection of the THP group then gives an intermediate which can be treated with a base and an alkylating agent R 2 I to give a mixture of indazole nitrogen alkylated isomers Xllla and Xlllb, typically favoring isomer Xllla.
  • R 2 I alkylating agent
  • the individual isomers XXXIa and Xlllb can be converted as described in Scheme 1 to the corresponding N-alkyl indazole isomer compounds captured in Formula (I).
  • Step 2 5-(tert-butyldimethylsilylox -3-iodo-lH-indazole
  • Step 4 (R/S) methyl 5-(tert-butyldimethylsilyloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole-3-carboxylate
  • Step 5 (R/S) (5-(tert-butyldimethylsilyloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-
  • Step 6 (R/S) 5-(tert-butyldimethylsilyloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole- 3-carbaldehyde
  • Step 8 5- so-butoxy-l-(tetrahyd -2H-pyran-2-yl)-lH-indazole-3-carbaldehyde
  • Step 9 (R/S) tert-butyl 2-(((5- so-butoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methyl)(methyl)amino)ethyl)carbamate
  • Step 10 ⁇ -((S-iso-butoxy-lH-indazol-S-y ⁇ methy ⁇ - ⁇ -methylethane-l ⁇ -diamine (Compound 2)
  • Step 1 (R/S) 5- so-butoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carbaldehyde
  • 3467512-1 was concentrated under vacuum and the pH value of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with 3x50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 60-100% of ethyl acetate in petroleum ether to yield 110 mg (61%) of 5-wo-butoxy-lH- indazole-3-carbaldehyde as a yellow solid.
  • the crude product (70mg) was purified by Pre-HPLC with the following conditions (1#-Pre-HPLC- 005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 ⁇ , 19x150mm; mobile phase, water with lOmmol NH 4 HCO 3 and CH 3 CN (18% CH 3 CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 35 mg (30%) of 5-iso- butoxy-l-methyl-lH-indazole-3-carbaldehyde as a white solid.
  • Step 5 ⁇ -((S-iso-butoxy-l-methyl-lH-indazol -y ⁇ methy ⁇ - ⁇ -dimethylethane-l ⁇ - diamine (Compound 3)
  • Step 1 (R/S) 5-(2-methoxyethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3- carbaldehyde
  • Step 2 (R/S) tert-butyl 2-(((5-(2-methoxyethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 3 N 1 -((5-(2-methoxyethoxy)-lH-indazol-3-yl)methyl)-N 1 ⁇ V 2 -dimethylethane-l,2- diamine (Compound 5)
  • Step 1 (R/S) 5-(4-nitrophenoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3- carbaldehyde
  • Step 3 (R/S) tert-butyl 2-(((5-(4-aminophenoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 4 (R S) tert-butyl methyl(2-(methyl((5-phenoxy-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methyl)amino)ethyl)carbamate
  • Step 5 ⁇ -dimethyl- ⁇ -iiS-phenoxy-lH-indazol-S-y ⁇ methy ⁇ ethane-l ⁇ -diamine (Compound 10)
  • Step 1 tert-butyl methyl(2-(methyl((5-((tetrahydrofuran-3-yl)oxy)-l-tosyl-lH-indazol- 3-yl)methyl)amino)ethyl)carbamate
  • Step 2 tert-butylmethyl(2-(methyl((5-((tetrahydrofuran-3-yl)oxy)-lH-indazol-3- yl)methyl)amino)ethyl)carbamate
  • Step 3 N 1 , N 2 -dimethyl-N 1 -((5-((tetrahydrofuran-3-yl)oxy)-lH-indazol-3-yl)methyl) ethane-l,2-diamine (Compoun
  • Step 4 5-iodo-l-(tetrahydro-2H-pyr -2-yl)-lH-indazole-3-carbaldehyde
  • Step 5 tert-butyl (2-(((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 6 tert-butyl (2-(((5-(3-chlorophenoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 7 N 1 -((5-(3-chlorophenoxy)-lH-indazol -yl)methyl)-N 1 ,N 2 -dimethylethane-l,2- diamine (Compound 27)
  • Step 2 tert-butyl methyl(2-(methyl((5-((tetrahydro-2H-pyran-4-yl)oxy)-lH-indazol-3- yl)methyl)amino)ethyl)carbamate
  • Step 3 N 1 , N 2 -dimethyl-N 1 -((5-((tetrahydro-2H-pyran-4-yl)oxy)-lH-indazol-3- yl)methyl)ethane-l,2-diamine (Compound 29)
  • Step 2 N,5-dimethoxy-N-methyl- -indazole-3-carboxamide
  • Step 3 N,5-dimethoxy-N-methyl- -tosyl-lH-indazole-3-carboxamide
  • N,5-Dimethoxy-N-methyl-lH-indazole-3-carboxamide (17g, 0.072mol) was dissolved in 200ml of dry THF and cooled to 0°C.
  • Triethylamine (20ml, 0.144mol) was added dropwise at 0°C and then after 10 min tosylchloride (15.12g, 0.079mol) was added. This reaction mixture was stirred at 90°C for 5 hrs. After completion of the reaction, the reaction mixture was cooled to room temprature and diluted with 200ml water and exctrated
  • N,5-Dimethoxy-N-methyl-l-tosyl-lH-indazole-3-carboxamide (25g, 0.064mol) was dissolved in dry THF (200ml) and cooled to -60°C.
  • LAH (1.21g, 2M in THF, 0.032mol) was added at -60°C slowly over a period of 30min.
  • the reaction mixture was stirred at -30°C for 2 hrs. After completion of the reaction, the reaction mixture was again cooled to -78°C and quenched with 500ml of water.
  • the reaction mixture was brought to room temperature and extracted with ethyl acetate (100mlx3). The ethyl acetate fractions were combined, dried over Na 2 S0 4 and distilled under reduced pressure to afford pure title compound (20g).
  • Step 7 tert-butyl (2-(((5-hydroxy-lH-indazol-3-yl)methyl)(methyl)amino)ethyl)(methyl) carbamate
  • Step 8 3-((methyl(2-(methylamino)ethyl)amino)methyl)-lH-indazol-5-ol (Compound 36)
  • ethyl) (methyl)carbamate 70mg was dissolved in 2ml methanolic HQ and the reaction mixture stirred at 40°C for 3 hrs. After completion of the reaction, the excess methanol was distilled off and the crude material was triturated with diethyl ether to afford pure title compound as HC1 salt. (40mg, 81.56%), LCMS: 99.05% (m/z) 235.48 (M++1), HPLC: 98.67%.
  • Pent-4-en-l-ol (150mg, 1.74mmol) was dissolved in THF (2 ml) and 4-methyl morpholine-N-oxide (190mg, 1.74mmol) and Os0 4 (0.1ml - 5% aqueous solution) were added at room temperature and the reaction mixture allowed to stir for 3 hours.
  • the reaction
  • Step 2 3-(2,2-dimethyl-l,3-dioxola -4-yl)propan-l-ol
  • Pentane-l,2,5-triol (170mg, 0.81mmol) and PTSA (30mg, 0.20mmol) were dissolved in 2,2-dimethoxy propane (2.5ml) and allowed to stir at ambient temperature for 3 hr. The reaction mixture was quenched with 50ml of water and extracted with ethyl acetate (50mlx2). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude material which was purified by Combi-flash using 50% ethyl acetate in hexane as eluent. Pure fractions were concentrated to give title compound (80mg, Yield: 35.39%).
  • Step 3 3-(2,2-dimethyl-l,3-dioxola -4-yl)propyl methanesulfonate
  • Step 4 tert-butyl 3-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino) methyl)-4-(3-(2,2-dimethyl-l,3-dioxolan-4-yl)propoxy)-lH-indazole-l-carboxylate
  • Step 5 5-((3-((methyl(2-(methylamino)ethyl)amino)methyl)-lH-indazol-4- yl)oxy)pentane-l,2-diol (Compound 41)
  • Step 1 tert-butyl (2-(((5-isopropyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 2 ⁇ -((S-isopropyl-lH-indazol-S-y ⁇ methy ⁇ - ⁇ -dimethylethane-l ⁇ -diamine (Compound 42)
  • Step 2 ⁇ -((S-iS-azaspiroCS.Slundecan-S- ⁇ -l-itetrah dro ⁇ H-p ran ⁇ - ⁇ -lH-indazol- S-y ⁇ methy ⁇ - ⁇ -iill-methy ⁇ ill-oxidany ⁇ borany ⁇ - ⁇ -dimethylethane-l ⁇ -diamine
  • Step 3 ⁇ -((S-iS-azaspiroCS.Slundecan-S- ⁇ -lH-indazol-S- ⁇ meth l)- ⁇ 1 , ⁇ 2 - dimethylethane-l,2-diamine (Compound 43)
  • Step 5 tert-butyl (2-(((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • reaction mixture was then cooled to 0°C and sodium cyanoborohydride (4.7g, 74.4mmol) was added portion wise at 0°C and stirring continued for lh.
  • the reaction progress was monitored by TLC. After completion of the reaction, it was diluted with water and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried over sodium sulphate and distilled under reduced pressure to get the crude
  • Step 6 tert-butyl (2-(((5-(3,6-dihydro-2H-pyran-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate
  • Step 7 tert-butyl methyl(2-(methyl((l-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H- pyran-4-yl)-lH-indazol-3-yl)methyl)amino)ethyl)carbamate N,5-dimethoxy-N-methyl- lH-indazole-3-carboxamide

Abstract

La présente invention concerne des composés de Formule (I), leurs sels pharmaceutiquement acceptables, et des compositions pharmaceutiques de ceux-ci. Les composés selon la présente invention sont utiles pour inhiber l'activité de l'arginine méthyltransférase. Des procédés d'utilisation des composés pour le traitement de troubles médiés par l'arginine méthyltransférase sont également décrits.
PCT/US2014/029750 2013-03-14 2014-03-14 Inhibiteurs de l'arginine méthyltransférase et utilisations de ceux-ci WO2014153235A2 (fr)

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